Anabolism of purine is a kind of prevalent and important biological metabolism in organisms. Its metabolic products, AMP and GMP, provide not only starting materials for biosynthesis of DNA and RNA in the organisms, but also purine bases which are necessary for synthesis of many key coenzymes (NAD, NADP, FAD and CoA), signal molecules (e.g., cAMP) and an important energy molecule ATP in the body. It is thus evident that the anabolism of purine lies in the core position of the whole metabolic network. Purine synthesis includes two synthetic pathways, i.e. de novo purine synthesis and salvage pathway.
Adenylosuccinatelyase deficiency (ADSL deficiency) is one metabolic disease which has deletion or disorder in de novo adenine synthesis and purine nucleotide metabolic pathway. This disease is primarily caused by the mutation or deletion of adenylosuccinatelyase in the patients, which results in the substrate SAICAR of this enzyme is unduly accumulated in cells and cannot be eliminated in time [Jaeken J, Van den Berghe G. (1984). An infantile autistic syndrome characterized by the presence of succinylpurines in body fluids. Lancet 8411:1058-1061.]. In 1984, Jaeken and Van den Berghe first detected the accumulation of this metabolite in body fluids of several patients with bradykinesia and autism. The patients with adenylosuccinatelyase deficiency usually develop symptoms such as severe dysplasia, bradykinesia, dull-looking, epilepsy, autism and the like [Spiegel, E. K., Colman, R. F., and Patterson, D. (2006). Adenylosuccinatelyase deficiency. Mol Genet Metab 89, 19-31. Clamadieu, C., Cottin, X., Rousselle, C., and Claris, O. (2008). Adenylosuccinatelyase deficiency: an unusual cause of neonatal seizure. Arch Pediatr 15, 135-138. Castro, M., Perez-Cerda, C., Merinero, B., Garcia, M. J., Bemar, J., Gil Nagel, A., Torres, J., Bermudez. M., Garavito, P., Marie. S., et al. (2002). Screening for adenylosuccinatelyase deficiency: clinical, biochemical and molecular findings in four patients. Neuropediatrics 33, 186-189. Jurecka, A., Zikanova, M., Tylki-Szymanska, A., Krijt, J., Bogdanska, A., Gradowska, W., Mullerova, K., Sykut-Cegielska, J., Kmoch. S., and Pronicka, E. (2008b). Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinatelyase deficiency. Mol Genet Metab 94, 435-442.].
ADSL deficiency has 3 types of continuous main phenotypes: neonatal lethal type, severe (type I) and mild-to-moderate (type II). It was clinically found that patients can have different phenotypes even they are from the same family. The oneset of the disease is generally from birth to infancy. The reported cases include lethal neonatal encephalopathy (manifested as hypokinesia, intractable epilepsy, respiratory disturbance), and moderate mental deficiency. All the patients have mental deficiency, and most of the patients have different types of epilepsy, and about one third of the patients have autism characteristics (unable to make eye contact, sensitive to sound and light, repetitive behaviors, agitation, temper tantrum, self-injury and self-mutilation). Other unusual clinical manifestations include psychomotor delay, overactivity, language disorder, hypotonia, muscular atrophy and spasm. Patients with severe ADSL deficiency usually have microcephaly. It has been reported that prenatal clinical manifestations include intrauterine growth retardation, microcephaly, fetal hypokinesia and absent of fetal heart rate variability.
In the metabolic pathway of adenine de novo synthesis, adenylosuccinatelyase (hereinafter referred to as ADSL enzyme) mainly participates in the catalytic cracking of SAICAR to form AICAR and in the reaction for generating AMP from S-AMP [Spiegel, E. K., Colman. R. F. and Patterson, D. (2006). Adenylosuccinatelyase deficiency. Mol Genet Metab 89, 19-31. Clamadieu. C., Cottin, X., Rousselle. C., and Claris. O. (2008). Adenylosuccinatelyase deficiency: an unusual cause of neonatal seizure. Arch Pediatr 15, 135-138. Castro. M., Perez-Cerda, C., Merinero, B., Garcia. M. J., Bemar. J., Gil Nagel, A., Torres. J., Bermudez. M., Garavito. P., Marie. S., et al. (2002). Screening for adenylosuccinatelyase deficiency: clinical. biochemical and molecular findings in four patients, Neuropediatrics 33, 186-189.]. In the patients with adenylosuccinatelyase deficiency, the harmful metabolite SAICAR cannot be eliminated in time due to the mutation or deletion of the ADSL enzyme, which usually makes the patients develop severe neurological and physiological symptoms, such as epilepsy, encephalodysplasia, bradykinesia and the like [Ciardo, F., Salerno. C., and Curatolo, P. (2001). Neurologic aspects of adenylosuccinatelyase deficiency. J Child Neurol 16, 301-308. Gitiaux, C., Ceballos-Picot. I., Marie. S., Valayannopoulos, V., Rio, M., Verrieres, S., Benoist. J. F., Vincent, M. F., Desguerre, I., and Bahi-Buisson, N. (2009). Misleading behavioural phenotype with adenylosuccinatelyase deficiency. Eur J Hum Genet 17, 133-136. Mierzewska. H., Schmidt-Sidor, B., Jurkiewicz, E., Bogdanska, A., Kusmierska. K., and Stepien, T. (2009). Severe encephalopathy with brain atrophy and hypomyelination due to adenylosuccinatelyase deficiency—MRI, clinical, biochemical and neuropathological findings of Polish patients. Folia Neuropathol 47. 314-320.]. A large amount of intermediate metabolites SAICAr, which is a product of the dephosphorylation of SAICAR, and S-Ado, which is a product of the dephosphorylation of S-AMP, are usually accumulated in the cerebrospinal fluid and body fluid of the patients [Spiegel, E. K., Colman, R. F., and Patterson, D. (2006). Adenylosuccinatelyase deficiency. Mol Genet Metab 89, 19-31. Mierzewska, H., Schmidt-Sidor, B., Jurkiewicz, E., Bogdanska, A., Kusmierska. K., and Stepien, T. (2009). Severe encephalopathy with brain atrophy and hypomyelination due to adenylosuccinatelyase deficiency—MRI, clinical, biochemical and neuropathological findings of Polish patients. Folia Neuropathol 47, 314-320.]. Van den Berghe et al. found that the ratio of S-do to SAICAr in the body fluid has certain correlation with the disease severity of the patient [Van den Bergh F, Vincent M F. Jaeken J, Van den Berghe G. (1993). Residual adenylosuccinase activities in fibroblasts of adenylosuccinase-deficient children: parallel deficiency with adenylosuccinate and succinyl-AICAR in profoundly retarded patients and non-parallel deficiency in a mildly retarded girl, J. Inherit. Metab. Dis. 16(2) 415-424.]. Until now, there is no clinically effective therapeutic regimens which can cure ADSL deficiency.
Phosphoribosylaminoimidazolesuccinocarboxamide synthetase/phosphoribosylaminoimidazole carboxylase, i.e. PAICS, is an important bifunctional enzyme in the purine de novo synthetic pathway. It has functions of SAICAR synthetase (4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase, SAICARs) and AIR carboxylase (5-aminoimidazole ribonucleotide carboxylase, AIRc), and can catalyze the sixth and seventh steps of the reaction of purine de novo anabolism, in which one key reaction process is shown as follows

Preceding researches of the inventors show that the accumulation of SAICAR and SAICAr can be effectively reduced by interfering with the function of PAICS protein (gene), thereby achieving the goal of treating or improving ADSL deficiency. However, no compound has been reported to have such effect at present.
Spermine
is a kind of polyamine substances which contains two amino groups and two imino groups. Spermine is obtained from putrescine (butanediamine) and S-adenosyl methionine through catalysis with various enzymes in organisms. Both spermine and spermidine are present in bacteria and most animal cells, and are important substances for promoting cell proliferation. Under acidic condition, it exhibits the characteristics of polycation polyamines and can bind with DNA molecules in viruses and bacteria to make the DNA molecules more stable and flexible. In addition, it is also one of necessary components in cell culture media. Therefore, spermine has been used as a nutritional supplement.